Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotide cyclic adenosine monophosphate (cAMP) into adenosine 5′-monophosphate (AMP). The cyclic nucleotide cAMP is synthesized by adenylyl cyclase, and serves as a secondary messenger in various cellular pathways.
cAMP functions as a second messenger regulating many intracellular processes within the body. An example is in the neurons of the central nervous system, where the activation of cAMP-dependent kinases and the subsequent phosphorylation of proteins is involved in acute regulation of synaptic transmission as well as neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP. There are at least ten families of adenylyl cyclases, and eleven families of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron.
A principal mechanism for regulating cyclic nucleotide signaling is via phosphodiesterase-catalyzed cyclic nucleotide catabolism. The 11 known families of PDEs are encoded by 21 different genes; each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors. Furthermore, PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE isozymes may offer particular therapeutic effects, fewer side effects, or both (Deninno, M., Future Directions in Phosphodiesterase Drug Discovery. Bioorganic and Medicinal Chemistry Letters 2012, 22, 6794-6800).
The present invention relates to compounds having a binding affinity for the fourth family of PDEs (i.e., PDE4A, PDE4B, PDE4C, and PDE4D), and, in particular, a binding affinity for the PDE4B isoform. In addition to affinity for the PDE4B isoform, the compounds of the present invention also have affinity for the PDE4A and PDE4C isoforms.
The PDE4 isozymes are characterized by selective, high-affinity hydrolytic degradation of the second messenger cyclic adenosine 3′,5′-monophosphate (cAMP), and by sensitivity to inhibition by Rolipram™ (Schering AG); beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models. A number of other PDE4 inhibitors have been discovered in recent years. For example, Roflumilast (Daliresp®), marketed by Forest Pharmaceuticals, Inc., is approved for severe chronic obstructive pulmonary disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms (exacerbations). Apremilast (Celgene Corp.) is in Phase III development and clinical trials have shown apremilast to be effective for the treatment of psoriasis (Papp, K. et al., Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet 2012; 380(9843):738-46).
While beneficial pharmacological activity of PDE4 inhibitors has been shown, a common side-effect of these treatments has been the induction of gastrointestinal side effects such as nausea, emesis, and diarrhea, which is currently believed to be associated with inhibition of the PDE4D isoform. Attempts were made to develop compounds with an affinity for the PDE4B isoform over the PDE4D isoform (See: Donnell, A. F. et al., Identification of pyridazino[4,5-b]indolizines as selective PDE4B inhibitors. Bioorganic & Medicinal Chemistry Letters 2010; 20:2163-7; and Naganuma, K. et al., Discovery of selective PDE4B inhibitors. Bioorganic & Medicinal Chemistry Letters 2009; 19:3174-6). However, there remains a need to develop PDE4 inhibitors, especially those having an affinity for the PDE4B isoform. In particular, there remains a need to develop compounds that have enhanced binding affinity for the PDE4B isoform over the PDE4D isoform for the treatment of various diseases and disorders of the central nervous system (CNS). The discovery of selected compounds of the present invention addresses this continued need, and provides additional therapies for the treatment of various diseases and disorders of the central nervous system (CNS), as well as metabolic, autoimmune and inflammatory diseases or disorders. Such diseases and disorders include, but are not limited to, neurodegenerative or psychiatric disorders, including psychosis, impaired cognition, schizophrenia, anxiety, depression (e.g., major depressive disorder), dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, muscular dystrophy, sickle cell disease and diabetes.
Treatment with the PDE4B inhibitors of the present invention may also lead to a decrease in gastrointestinal side effects (e.g., nausea, emesis and diarrhea) believed to be associated with inhibition of the PDE4D isoform (Robichaud, A. et al., Deletion of Phosphodiesterase 4D in Mice Shortens α2-Adrenoreceptor-Mediated Anesthesia, A Behavioral Correlate of Emesis. Journal of Clinical Investigation 2002, Vol. 110, 1045-1052).
In addition to the development of compounds having affinity for the PDE4B isoform, there remains a need to develop compounds having an affinity for the PDE4A and PDE4C isoforms. The discovery of selected compounds of the present invention having affinity for the PDE4A and PDE4C isoforms also provides for the treatment of various diseases and disorders of the central nervous system (CNS), as well as treatment for various metabolic, autoimmune and inflammatory diseases or disorders.